Biology subjects

Winkelman, B. H. J.

Publications and source records attributed to Winkelman, B. H. J..

4 recordsLinked to original sources

bioRxiv2025

Dopaminergic Control of Retinal Oscillations Driving Infantile Nystagmus

Infantile nystagmus is a debilitating involuntary eye movement disorder often associated with retinal diseases such as Congenital Stationary Night Blindness (CSNB). The oscillating eye movements of infantile nystagmus come with reduced visual acuity, strongly impairing quality of life. No cure exists for this condition. Previously, we demonstrated that nystagmus in the CSNB mouse model Nyxnob has a retinal cause. Specifically, we found that synchronized oscillations of retinal ganglion cells (RGCs) are transmitted to the accessory optic system, triggering compensatory eye movements. The RGC oscillations appear to originate from a specific retinal cell type, the AII amacrine cell (AII AC), making these cells the preferred target for treatment. Here we found that pharmacologically activating the dopaminergic input to AII ACs in Nyxnob mice completely suppresses the pathological oscillations of both AII ACs and RGCs and improves the signal fidelity of RGCs. Moreover, our retinal network simulations confirm that the experimentally observed changes to AII AC voltage-gated currents are sufficient to account for the dopamine-dependent abolishment of these oscillations. Our findings provide a novel mechanistic understanding of the retinal mechanism underlying infantile nystagmus as well as the associated low visual performance. Consequently, they offer the first pharmacological therapeutic strategy for this disorder. SignificanceOscillatory eye movements in infantile nystagmus arise from abnormal retinal activity, yet the cellular basis of this instability has remained unclear. Here we show that this abnormal activity stems from disrupted dopaminergic modulation. By defining how dopamine regulates the activity of a key retinal cell type, the AII amacrine cell, we demonstrate that restoring dopamine levels can return the retinal circuit to a stable state and improve the clarity of visual signals leaving the eye. This work links neuromodulation to retinal circuit instability and identifies dopaminergic control of AII amacrine cells as a pharmacologically targetable point of intervention. These findings suggest a retina-focused pharmacological treatment strategy for infantile nystagmus, a disorder that currently lacks effective therapeutic options.

neuroscience↗

bioRxiv2023

The sleep quality- and myopia-linked PDE11A-Y727C variant impacts neural physiology by reducing catalytic activity and altering subcellular compartmentalization of the enzyme

Recently, a Y727C variant in the dual-specific 3,5-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if 1) PDE11A protein is expressed in the retina or other eye segments in mouse, 2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and 3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT--but not KO mice--that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness, axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

neuroscience↗

bioRxiv2023

A Common Cause for Nystagmus in Different Congenital Stationary Night Blindness Mouse Models

In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), synchronous oscillating retinal ganglion cells (RGCs) lead to oscillatory eye movements, i.e., nystagmus. Given the distribution of mGluR6 and Cav1.4 in the retina as well as their clinical association with CSNB, we hypothesize that mGluR6-/- and Cav1.4-/- mutants show, like the Nyxnob mouse, oscillations that originate in the AII amacrine cells (AII ACs). Using eye movement and multi-electrode array (MEA) recordings of RGCs we show that the nystagmus as well as the underlying RGC oscillations are also present in mGluR6-/- and Cav1.4-/- mice. Yet, we find that the oscillations in the mGluR6-/- and Cav1.4-/- mutants slightly differ from each other and also from those of the Nyxnob mice. Moreover, each of the three mutations likely impacts the membrane potential of the AII ACs differently. Together our results indicate that nystagmus and oscillating RGCs are generalizable features associated with CSNB mutations localized at the photoreceptor-bipolar cell synapse.

neuroscience↗

bioRxiv2019

Nystagmus in patients with congenital stationary night blindness (CSNB) originates from synchronously firing direction-selective retinal ganglion cells

Congenital nystagmus, involuntary oscillating small eye movements, is commonly thought to originate from aberrant interactions between brainstem nuclei and foveal cortical pathways. Here we investigated whether nystagmus associated with congenital stationary nightblindness (CSNB) can result from primary deficits in the retina. We found that CSNB patients as well as an animal model (nob mice), both of which lack functional nyctalopin protein (NYX, nyx) in ON bipolar cells (ON-BC) at their synapse with photoreceptors, showed oscillating eye movements at a frequency of 4-7Hz. nob ON direction selective ganglion cells (ON-DSGC), which detect global motion and project to the accessory optic system (AOS), oscillated with the same frequency as their eyes. In the dark, individual ganglion cells (GC) oscillated asynchronously, but their oscillations became synchronized by light stimulation. Likewise, both patient and nob mice oscillating eye movements were only present in the light. Retinal pharmacological manipulations that blocked nob ON-DSGC oscillations also eliminated their oscillating eye movements, and retinal pharmacological manipulations that reduced oscillation frequency of nob ON-DSGCs also reduced oscillation frequency of their eye movements. We conclude that, in nob mice, oscillations of retinal ON-DSGCs cause nystagmus with properties similar to those associated with CSNB in humans. These results show that the nob mouse is the first animal model for a form of congenital nystagmus paving the way for development of therapeutic strategies.

neuroscience↗